title: Central apelin controls glucose homeostasis via a nitric oxide-dependent pathway in mice.
abstract: OBJECTIVE
  Apelin and its receptor have emerged as promising targets for the treatment of insulin resistance. Indeed, peripheral administration of apelin stimulates glucose utilization and insulin sensitivity via a nitric oxide (NO) pathway. In addition to being expressed on peripheral metabolically active adipose tissues, apelin is also found in the brain. However, no data are available on the role of central effects of apelin on metabolic control. We studied glucose metabolism in response to acute and chronic intracerebroventricular (i.c.v.) injection of apelin performed in normal and obese/diabetic mice.
  
  
  RESULTS
  We demonstrate that i.c.v. injection of apelin into fed mice improves glucose control via NO-dependent mechanisms. These results have been strengthened by transgenic (eNOS-KO mice), pharmacological (L-NMMA i.c.v. treated mice), and real-time measurement of NO release with amperometric probes detection. High-fat diet-fed mice displayed a severely blunted response to i.c.v. apelin associated with a lack of NO response by the hypothalamus. Moreover, central administration of high dose apelin in fasted normal mice provoked hyperinsulinemia, hyperglycemia, glucose intolerance, and insulin resistance.
  
  
  CONCLUSIONS
  These data provide compelling evidence that central apelin participates in the regulation of glucose homeostasis and suggest a novel pathophysiological mechanism involved in the transition from normal to diabetic state.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1048, Toulouse, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Duparc
authors.forename: André
authors.initials: A
authors.lastname: Colom
authors.forename: Patrice D
authors.initials: PD
authors.lastname: Cani
authors.forename: Nicolas
authors.initials: N
authors.lastname: Massaly
authors.forename: Sophie
authors.initials: S
authors.lastname: Rastrelli
authors.forename: Anne
authors.initials: A
authors.lastname: Drougard
authors.forename: Sophie
authors.initials: S
authors.lastname: Le Gonidec
authors.forename: Lionel
authors.initials: L
authors.lastname: Moulédous
authors.forename: Bernard
authors.initials: B
authors.lastname: Frances
authors.forename: Isabelle
authors.initials: I
authors.lastname: Leclercq
authors.forename: Catherine
authors.initials: C
authors.lastname: Llorens-Cortes
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Pospisilik
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Delzenne
authors.forename: Philippe
authors.initials: P
authors.lastname: Valet
authors.forename: Isabelle
authors.initials: I
authors.lastname: Castan-Laurell
authors.forename: Claude
authors.initials: C
authors.lastname: Knauf
mesh_terms: D054392:Adipokines; D000818:Animals; D000073861:Apelin; D053898:Biosynthetic Pathways; D001921:Brain / Q000378:metabolism; D002940:Circadian Rhythm; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D057967:Infusions, Intraventricular; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*
chemical_list: D054392:Adipokines; D000073861:Apelin; C402826:Apln protein, mouse; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D009569:Nitric Oxide; D005947:Glucose